Thieno(3,4-d)pyrimidines

ABSTRACT

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULA:   1-R3,5-R1,7-R2-THIENO(3,4-D)PYRIMIDINE   WHEREIN: R1 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF CHLORO AND PROPYL, R2 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF MORPHOLINO, 2-METHYL-MORPHOLINO AND 3-METHYLMORPHOLINO, AND R3 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND METHYL, AND THE ADDITION SALTS THEREOF WITH PHARMACEUTICALLY ACCEPTABLE ACIDS.

United States Patent US. Cl. 260-247.]; L 6 Claims ABSTRACT OF THEDISCLOSURE 'Ihieno[3,4-d]pyrimidines of the general formula:

Illa

wherein R is hydrogen, halogen, alkyl, alkoxy, amino, alkylamino,allylamino, hydroxy-alkylamino, cycloalkylamino, phenylamino,dialkylarnino, di(hydroxyalkyl)- amino, alkyl-hydroXyalkyl-amino,pyrrolidino, piperidino, alkylpyrrolidino, alkylpipericlino, morpholino,alkyl-Z- morpholino, alkyl-3-morpholino, dialkyl-3,5-morpholino,N-methylpiperazino, all said alkyl having 1 to 7 carbon atoms, saidalkoxy having 1 to 5 carbon atoms and said cycloalkyl having 3 to 6carbon atoms, R has the same meanings as R except alkyl and with theproviso that R is other than hydrogen or halogen when R representshydrogen or halogen and R is hydrogen or alkyl having 1 to 7 carbonatoms, as Well as the addition salts thereof with pharmaceuticallyacceptable acids are, in particular, active on the cardiovascularsystem. Processes for their preparation are given.

The invention relates to new thieno[3,4-d]pyrimidines corresponding tothe general formula (I):

R2 Rs 1 and their addition salts with pharmaceutically acceptable acids.

It also relates to the preparation of these compounds and their use asmedicaments, either alone or in association with appropriate excipients.

As used herein, the term alkyl designates straight or branch chainedradicals having 1 to 7 carbon atoms; the term alkoxy designates straightor branch chained radicals having 1 to 5 carbon atoms; and the termcycloalkyl designates radicals having 3 to 6, preferably 5 to 6 carbonatoms.

The thieno[3,4-d]pyrimidine system is a recent acquisition in chemistry.Synthesized for the first time by B. R.

Patented Nov. 26, 1974 Baker et al. (J. Org. Chem, 18 (1953), 138), ithas been prepared subsequently by R. Gomper et al. (Am, 659 (1962), andby Robba et a1. (OK, 267 (1968, No. 11), 697).

It will, however, be observed that the processes of synthesis used bythese authors only make it possible to obtain thieno[3,4-d]pyrimidin-4(3I-I)-ones unsubstituted in the 2-position. Furthermore thephysiological properties of the thieno[3,4-d]pyrimidin-4(3H)-ones thussynthesized have not been examined by their authors, except for theantimalarial activity of a thieno[3,4-d]pyrimidin- 4(3H)-onessubstituted on the lactam nitrogen atom.

The R R R -snbstituted thieno[3,4-d]pyrimidines in accordance with thepresent invention may be prepared by one or other of the followingprocesses:

(a) Reacting a 2,4-dihalo5-R -thieno[3,4-d]pyrimidinc of the formula(II) with a compound R M (III), in accordance with the equation:

In these formulae Hal=halogen,

M=H or an alkali or alkaline-earth metal,

R =unsubstituted amino, mono-substituted or di-substituted amino orheterocyclic radicals listed above when M=H, whereas when M is an alkali0r alkaline-earth metal, R =a C -C alkoxy radical,

R has the meaning given above.

(b) Hydrogenolyzing the 2-halo-4-R -5-R -thieno[3,4- d]pyrimidine of theformula (IV), to obtain the corresponding 2-hydrogenated compoundaccording to the equation:

R2 2 B A B5 N N t a t (I) in which R =R In these formulae R =alkoxy,unsubstituted amino, mono-substituted or disubstituted amino orheterocyclic radicals mentioned above,

Hal=halogen,

R, has the meaning given above.

t s S 1 AT Z 2 H 1W The absence of such a coupling consequently confirmsthe substitution in position 4.

3 (c) Reacting the 2-halo-4-R -5-R -thieno[3,4-d1pyrimidine of theformula (IV) with a compound R M (V) according to the equation:

In these formulae ((1) When in the formula (I) R and R are identical andrepresent an amino group, a mono-substituted or disubstituted aminogroup or the heterocyclic radicals mentioned above, reacting a2,4-dihalo-5-R -thieno[3,4-d] pyrimidine of the formula (II) with anexcess of amine of the formula R -H or R H (VI or VII) according to theequation:

In these formulae (VI) or (VII) (1) Ha1=halogen,

R =R =unsubstituted amino, mono-substituted or disubstituted amino orheterocyclic radicals mentioned above,

R has the meaning given above.

(e) When in the formula (I) R; and R are identical and represent a C -Calkoxy group, reacting a 2,4-dihalo- 5-R -thieno[3,4-d1pyrimidine of theformula (II) with an excess of an alkali metal or alkaline-earth metalalcoholate of the formula R M or R M (VIII or IX) according to theequation:

1131 Rich) N N s R1M(=R2M) s NJ-Ha1 J-mm) (II) (VIII) or (IX) (I) Inthese formulae OAlk R2 A R3 N N s J R21 1 s J OAlk N/ -0A1k (X) 1 inwhich v11 (XI) 1) in which R1=Rz=0Alk R =alkoxy In these formulae R=unsubstituted amino, monosubstituted or disubstituted amino orheterocyclic radicals mentioned above,

R has the meaning given above.

The identity of the products obtained by this process and of thoseobtained by process (c) in which R =alkoxy, justifies the reactionequations and formulae as they are proposed for this process.

(g) Reacting a 2-R -4-halo-5-R -thieno[3,4-d]pyrimidine of the formula(XII) with a compound R H (VII) according to the equation:

N (XII) (VII) In these formulae Hal=halogen,

R =loWer alkoxy, unsubstituted amino, mono-substituted or disubstitutedamino or heterocyclic radicals mentioned above,

R has the meaning given above.

The compounds according to the invention possess pharmaceuticalproperties of value, in particular cardiovascular, bacteriostatic andfungistatic effects.

The cardiovascular action was demonstrated particularly by the followingpharmacological test: the blood rate in the thoracic aorta (cardiacoutput), in the vertebral artery (cerebral flow) and in the femoralartery (musculocutaneous peripheral flow) was measured in the doganaesthetized with nembutal and subjected to artificial respiration.

The measurements were carried out by means of periarterial probesaccording to the principle of electromagnetic fiow measurement, Thegeneral experimental condi tions have already been described in theliterature (D. Wellens and E. Wauters, Arch. Int. Pharmacod, 171/1(1968), 246). The medicament was administered by intravenous route.

The administration of compounds according to the invention, namely the2-chloro-4-isopropylamino-thieno[3,4- d]pyrimidine monohydrochloride(compound A), the 2- chloro-4-morpholino-thieno[3,4-d1pyrimidinemonohydrochloride (compound B), the 2-chloro-4-(3-methyl-morpholino)thieno[3,4 d] pyrimidine monohydrochloride (compound C), the2-n-propylamino-4-isopropylaminothieno[3,4-d] pyrimidine monomaleate(compound D) and the 2-n-propyl-4-isopropylamino-thieno[3,4 d]pyrimidine mono-maleate (compound E) brought about the following effectsunder these conditions:

The compounds A, B and E, at a dose of 2 mg./ kg. animal body weight,bring about an appreciable increase in the cardiac, cerebral and femoralflows; the compounds C and D, administered at the same dose, bring aboutan appreciable increase in the cardiac flow and a marked increase in thecerebral and femoral flows; the cerebral circulation increases inparticular by 30 to 40% for at least 40 minutes. Respiratory analepticaction was demonstrated in rabbit, in morphinic respiratory depression.Under these conditions, the 2-ethoxy-4-isopropylamino-thieno[3,4-d]pyrimidine monohydrochloride (compound F) and the 2-ethoxy-4-n-propylamino-thieno 3,4-d] pyrimidine monohydrochloride(compound G), at the dose of 2.5 mg. of free a base/ kg. animal bodyweight, have an effect equivalent to that produced by a six times higherdose of diethylnicotinamide.

The intravenously administered lethal doses (LD were determined in ratand mouse. For compounds A to G mentioned above, the recorded results,expressed in mg. of compound per kg. of animal body weight, are given inthe following table:

The compounds according to the invention may be administered by oral,parenteral or rectal route, in association with a pharmaceutical supportor appropriate excipient.

Thus, in the case of oral administration, the forms may be solid orliquid and be presented in the form of capsules, coated or uncoatedtablets, dragees, solutions or suspensions, in association with thesupports or excipients generally used in pharmacy. The excipients fortablets include lactose, potato or corn starch, talcum, gelatin,cellulose, sugar, silica, magnesium or calcium stearate,polyvinylpyrrolidone and various colouring materials and aromas.

For parenteral administration, the support or excipient may be aparenterally acceptable sterile liquid, for example Water, a solution ofpolyvinylpyrrolidone, or again a parenterally acceptable oil, forexample groundnut oil.

For rectal administration, the support may be a base component forsuppositories, for example cocoa butter or a mixture of glycerides.

The forms of administration may be presented advantageusly in unitdoses.

The tablets, drages, capsules, ampoules and suppositories preferablycontain a unit dose of between 5 and 160 mg.

The solutions and suspensions preferably contain 0.1 to 1% by weight ofactive substance according to the invention, but they may contain up to10% by weight.

The examples which follow illustrate the present invention withoutlimiting it.

EXAMPLE 1 Preparation of 2-chloro-4-isopropylamino-thieno[3,4-d]

pyrimidine] 45 g. (0.22 moles) of 2,4-dichloro-thieno[3,4-d]pyrimidineare suspended in 1800 ml. of absolute ethyl alcohol. To the cooledmixture 28.5 g. (0.48 moles) of isopropylamine are added drop by dropwhilst agitating vigorously and maintaining the temperature at betweenand 5 C. A clear solution is obtained which is agitated for a furtherhour at ambient temperature. The solution is concentrated, making surethat the temperature of the bath does not exceed 30 C. The syrupyresidue is poured into iced water whilst agitating -well. A yellow solidis formed which is drained off, washed with water and dried. 49 g. ofZ-chloro- 4-isopropylamino-thieno 3 ,4-d] pyrimidine are obtained with ayield reaching 98% of theory. M.P.: 189-191 C.

Analysis-Calculated for C H ClN S (molecular WeightM.W.: 227.7)(percent): C, 47.49; H, 4.42; N, 18.44; Cl, 15.57; S, 14.08. Found(percent): C, 47.50; H, 4.64; N, 18.44; Cl, 15.32; S, 14.07.

This product is easily converted into the monohydrochloride in a knownmanner. M.P.: 220 C. (decomposes).

Analysi.r.Calculated for CgHmClNgS'HCI (M.W.: 264.1) (percent): N,15.89; C1, 26.84; S, 12.14. Found (percent): N, 15.70; Cl, 27.10; S,11.75.

The following compounds of the invention are prepared in the same way:

2-chloro-4-propylamino-thieno[3,4-d]pyridine; M.P. 134- 136 C.(recrystallized from toluene) 2-chloro-4-isobutylamino-thieno[3,4-d]pyrimidine;

64 C. (not recrystallized) 2-chloro-4- (sec-butylamino -thieno I 3,4-d]pyrimidine; M.P. 169 C. (recrystallized from toluene)2-chloro-4-[N-(1,5-dimethylhexyl)-amino]-thieno[3,4-

dJpyrimidine; M.P. ll0-113 C. (not recrystallized) 2-chloro-4- [N-l-hydroxymethyl-ethyl) amino] -thieno [3,4-d]pyrimidine; M.P. 177178 C.(not recrystallized) 2-chloro-4- [N-( 1-hydroxymethyl-2-hydroxy-ethylamino]-thieno[3,4-d]pyrimidine; M.P. 174-175 C. (recrystallized fromacetone) 2-chloro-4- diethylamino-thieno 3,4-d] pyrimidine; M.P. 96-97C. (recrystallized from ethyl acetate-hexane mixture) 2-chloro-4-[di(2-hydroxyethyl) -amino]-thieno [3 ,4-d]

pyrimidine; after recrystallization from acetone M.P. 145 C.(decomposes) 2-chloro4-cyclopentylamino-thieno 3,4-d] pyrimidine; M.P.148-1495 C. (recrystallized from benzene)2-chloro-4-cyclopropylamino-thieno[3,4-d] pyrimidine; afterrecrystallization from benzene M.P. 113 C. (decomposes)2-chloro-4-anilino-thieno[3,4-d]pyrimidine; M.P.

182 C. (recrystallized from benzene)2-chloro-4-pyrrolidino-thieno[3,4-d] pyrimidine; M.P.

131133 C. (not recrystallized)2-chloro-4piperidino-thieno[3,4-d]pyrimidine; M.P. 90-

94 C. (recrystallized from benzene) 2-chloro-4-morpholino-thieno [3,4-d]pyrimidine M.P.

133-135 C. (recrystallized from acetone) 2-chloro-4-(Z-methyl-morpholino -thieno [3,4-d] pyrimidine; M.P. 95100 C. (notrecrystallized) 2-chloro-4-( 3-methyl-morpholino -thieno 3,4-d]pyrimidine; M.P. 126-128 C. (recrystallized from toluene-hexane mixture)2-chloro-4- (4-methyl-piperazino -thieno [3,4-d1pyrimidine; M.P. 119-121C. (recrystallized from ethyl acetate-hexane mixture)2-chloro-4-morpholino-5-methyl-thieno[3,4-d]pyrin1- dine; M.P. of thehydrochloride 240 C. (decomposes) 2-chloro-4- 3-methyl-morpholino-5-methyl-thieno[3,4- djpyrimidine; M.P. of the hydrochloride 222 C.decomposes).

If desired, the excess of reactional amine, which serves to neutralizethe liberated hydrochloric acid, may in each case be replaced by an atleast equivalent amount of triethylamine.

The 2,4-dichloro-thieno[3,4-d1pyrimidine used as a raw material for thesynthesis of the compounds mentioned in Example 1 is a new compoundprepared by the chlorination of 2,4-dihydroxy-thieno[3,4-d]pyrimidinewith phosphorus oxychloride at reflux temperature in the presence ofN,N-diethylaniline. The obtained product melts at 122-- 128 C. It ispurified by sublimation in vacuo. A very pure product is thus obtainedwith a yield of 70% with respect to the amount of the starting dichlorocompound. M.P. 133-134 C.

Analysis. Calculated for C H CI N S (M.W. 205) (percent): C, 35.2; N,13.66; CI, 34.6; S, 15.64. Found (percent): C, 35.6; N, 13.66; Cl, 34.6;S, 15.54.

In turn, 2,4-dihydroxy-thieno[3,4-d]pyrimidine, which is also a newcompound, is obtained. by heating under reflux3-ureido-4-carbomethoxy-thiophene suspended in absolute ethyl alcoholwith concentrated hydrochloric acid for 4 hours. Yield: 65% M.P. 300 C.

Analysis.Calculated for C H N O S (M.W. 168.1) (percent): C, 42.8; H,2.40; N, 16.66; S, 19.05. Found (percent): C, 42.7; H, 2.67; N, 16.64;S, 19.30.

The 3-ureido-4-carbomethoxy-thiophene, which is also a new compound, isobtained in turn by adding an aqueous solution of potassium cyanate toan aqueous hydrochloric acid solution of3-amino-4-carbomethoxy-thiopl1ene hydrochloride. The reaction takesplace at room temperature with a yield of 80%. M.P.: goes brown at 165C. and melts at 197 C. with decomposition.

Analysis.-Calculated for C H N O S (M.W. 200.2) (percent): C, 42.0; H,4.03; N, 13.99. Found (percent): C, 42.3; H, 4.56; N, 13.53.

The 3-amino-4-carbomethoxy-thiophene hydrochloride is known from thearticle by B. R. Baker et al. in J. Org. Chem., 18, (1953), 138; it maybe prepared by the process described in this article.

EXAMPLE 2 Preparation of 2-chloro-4-ethoxy-thieno[3,4-d] pyrimidine 6.15g. (0.03 mole) of 2,4-dicholro-thieno[3,4-dlpyrimidine are suspended in250 ml. of absolute alcohol at C. Whilst agitating constantly a solutionof 0.03 mole sodium ethylate in ethyl alcohol is added drop by drop. Thespeed of addition is regulated in such a manner that the temperature ofthe reaction medium is maintained at between 0 and 5 C. One obtains aclear solution in which a precipitate is gradually formed. When theaddition is completed, the agitation is continued for a further 2 hoursat ordinary temperature. The reaction mixture is then poured into 2litres of iced water and the precipitate formed is filtered off, washedwith water and then dried in vacuo. After recrystallization fromtoluene, 5.2 g. of 2-chloro-4-ethoxy-thieno[3,4-d] pyrimidine areobtained (81% of theory). M.P. 136-140 C.

Analysis.Calculated for C H CIN OS (M.W. 214.7) (percent): C, 44.7; H,3.28; N, 13.03; S, 14.94; Cl, 16.51. Found (percent): C, 44.2; H, 3.52;N, 13.13; S, 14.95; Cl, 16.70.

EXAMPLE 3 Preparation of 4-isopropylamino-thieno[3,4-d] pyrimidine g. ofzinc powder are introduced into a solution of 3.9 g. (0.017 moles) of2-cho1r0-4-isopropylarnino-thieno [3,4-dlpyrimidine in 150 ml. ofabsolute ethyl alcohol. ml. of glacial acetic acid are then added dropby drop whilst agitating. When the addition is completed, the agitationis continued for a further 36 hours at ordinary temperature. Thereaction mixture is filtered over Hyflocel and the filtrate is pouredinto 700 ml. of iced water. The pH of the solution is adjusted to 8 Withsodium hydroxide and it is extracted several times with ether. The etherphase is Washed with water to pH 7, it is dried over sodium sulfate andit is then evaporated to dryness. 1.9 g. of4-isopropylamino-thieno[3,4-d]pyrimidine, still containing a little ofthe initial product, are obtained. After chromatographic separation andrecrystallization from ethyl acetate, one obtains 0.8 g. (25% of theory)of the purified product which melts at 230 C. with decomposition.

Analysis.Calculated for C H N S (M.W. 193.28) (percent): C, 56.0; H,5.73; N, 21.72. Found (percent): C, 56.1; H, 5.88; N, 21.72.

EXAMPLE 4 Preparation of 2-n-propylamino-4-isopropylaminothieno[3,4-d]pyrimidine A solution of 13 g. (0.057 moles) of2-chloro-4-isopropylamino-thieno[3,4-d1pyri1nidine in 250 ml. ofnpropylamine, is heated in an autoclave at 140 C. for 6 hours. Thereaction solution is evaporated in vacuo and the solid residue is takenup in ether. It is bleached with active charcoal and the solvent is thendriven off in vacuo. After recrystallization from acetone, 9.05 g. of

8 2-n-propylamino-4-isopropylamino-thieno[3,4 d]pyrimidine (63% oftheory) are obtained. M.P. 1l6118 C.

The free base, dissolved in a minimum of ethyl alcohol, may be convertedinto the monomaleate by adding a concentrated solution of maleic acid inethyl alcohol, and then adding ether. 9.7 g. of maleate (73% of theory)are obtained. M.P. 189 C. (decomposes).

Alzalysis.Calculated for C H N S-1C H O (M.W. 366.4) (percent): C, 52.5;H, 6.06; N, 15.3; S, 8.75. Found (percent): C, 52.6; H, 6.08; N, 15.2;S, 8.99.

The base may also be converted into the monohydrochloride by dissolvingit in methyl alcohol, adding a solution of hydrochloric acid in methylalcohol and then ether. The product obtained has a melting point of 183-185 C.

A/2alysis.Calculated for C H N S1HCl (M.W. 2868) (percent): C, 50.2; H,6.67; N, 19.5. Found (percent): C, 49.8; H, 6.75; N, 19.1.

EXAMPLE 5 Preparation of 4-isopropylamino-2-morpholino-thieno [3,4-d]pyrimidine 6 g. (0.26 moles) of 2-chloro-4-isopropylamino-thieno[3,4-dlpyrimidine and 25 mls. of morpholine are mixed and then heatedunder reflux for 4 hours. The mixture is cooled and poured into Waterwith vigorous agitation; a brown solid appears, which is separated byfiltration, washed with water and put to dry. The product is convertedinto the maleate, which is recrystallized from acetone. The free base isobtained again by treatment with alkali and in thi way one obtains 3.4g. of pure product. M.P. 202 C. with decomposition.

Analysis.Calculated for C13H18N4OS (M.W. 278.4) (percent): C, 56.0; H,6.51; N, 20.1; S, 11.51. Found (percent): C, 55.9; H, 6.50; N, 20.0; S,11.63.

EXAMPLE 6 Preparation of 2,4-dimorpholino-thieno[3,4-d] pyrimidine(maleate) As in Example 1, 2,4-dichloro-thieno[3,4-d]pyrimidine is usedas the starting product and it is reacted with an excess of morpholineby heating under reflux. When the cooled reaction mixture is introducedinto water with agitation, a yellow solid separates out, which is washedwith Water and dried. The residue is dissolved in a minimum of benzeneand a concentrated ethanolic solution of maleic acid is added and thenether. The maleate which is precipitated is recrystallized from absoluteethyl alcohol. Yield reaches 40% of theory. M.P.: 225 C. (decomposes).

Analysis. Calculated for C H N O S-1C H O (M.W. 422.5) (percent): C,51.1; H, 5.25; N, 13.2; S, 7.58. Found (percent): C, 51.0; H, 5.32; N,13.1; S, 7.73.

EXAMPLE 7 By the methods described in Examples 4 to 6, it is alsopossible to obtain the following compounds of the invention:

2-n-butylamino-4-isopropylamino-thieno [3 ,4-d]

pyrimidine; M.P. of the maleate: 191 C. (decomposes)2,4-di(isopropylamino)-thieno[3,4-d]pyrimidine; M.P.

of the maleate: 174-176" C.

2-isobi1tylamino-4-isopropylamino-thieno [3 ,4-d]

pyrimidine; M.P. of the maleate: 195 C. (decomposes)2-(4-methyl-piperazino)-4-isopropylamino-thieno[3,4-d]

pyrimidine; M.P. of the free base: 148 C.;

M.P. of the dimaleate: 190 C. (decomp.)2-anilino-4-isopropylamino-thieno[3,4-d]pyrimidine;

M.P. of the maleate: 260 C. (decomposes) 2,4di (n-propylamino) -thieno[3,4-d] pyrimidine; M.P.

of the maleate: C. (decomposes) 2- (4-methyl-piperazino)-4-n-propylamino-thieno 3 ,4-d] pyrimidine; M.P. of the free base:177l80 C.; M.P. of the dihydrochloride: 296 C. (decomp.)

2-n-propylamine-4-isobutylamino-thieno[3,4-d]

pyrimidine; MP. of the maleate: 181-182 C.

2-n-propylamino-4-sec-butylamino-thieno 3 ,4-d]

pyrimidine; M.P. of the free base: 147-149 C.

2-n-propyl amino-4-diethylamino-thieno [3 ,4-d]

pyrimidine; M.P. of the free base: 115-119 C.

2-n-propylamino-4-cyclopentylaminothieno [3 ,4-d]

pyrimidine; M.P. of the maleate: 178 C. (decomposes)2-n-propylamino-4-pyrrolidino-thieno 3,4-d] pyrimidine;

M.P. of the maleate: 184 C. (decomposes)2-npropylamino-4-morpholino-thieno [3 ,4-d] pyrimidine;

M.P. of the maleate: 181-183 C.

2- (4-methyl-piperazino -4-morpholino-thieno [3,4-d]

pyrimidine; M.P. of the free base: 165-167 C.; M.P. of the dimaleate:210 C. (decomp.)

2-pyrrolidino-4-mo rpholino-thieno 3,4-d] pyrimidine;

M.P. of the maleate: 205 C. (decomposes) 2-n-propylamino-4- [N-(l'hydroxymethyl-ethyl) -amino] thieno[3,4-d] pyrimidine; M.P. of themaleate: 205 C. (decomposes) 2-n-propylamino-4- [N-1-hydroxymethyl-Z-hydroxyethyl)-amino]-thieno[3,4-d] pyrimidine; M.P. ofthe hydrochloride: 192 C. (decomp.)

2-ethylamino-4-isopropylamino-thieno [3 ,4-d pyrimidine;

M.P. of the maleate: 174175 C.

2,4-di(anilino)-thieno[3,4-d] pyrimidine; M.P. of the h drochloride: 245C. (decomposes).

EXAMPLE 8 Preparation of 4-isopropylamino-S-methyl-Z-npropylamino-thieno[3 ,4d] pyrimidine A solution of 12 g. (0.0496 moles) of2-chloro-4-isopropylamino-S-methyl-thieno[3,4-d]pyrimidine in 250 ml. ofn-propylamine is heated in an autoclave at 140 C. for 6 hours. Thereaction mixture is evaporated in vacuo, the residue is taken up inether and the insolubles are filtered off. After bleaching with activecharcoal, the solvent is driven off in vacuo. 16.3 g. of a dark redsyrup are obtained.

The maleate is prepared by dissolving the syrup in the minimum quantityof absolute ethyl alcohol, adding a concentrated ethanolic solution ofmaleic acid, and then ether. After recrystallization from acetone, 13.7g. (72% of theory) of4-isopropylamino-5-methyl-2-n-propylamino-thieno[3,4-d]pyrimidinemaleate are obtained. M.P. 178 C. (decomposes).

Analysis.Calculated for C13H20N4S'1C4H4O4 (M.W.

380.5) (percent): N, 14.72; C, 53.5; H, 6.31; S, 8.42. Found (percent):N, 14.68; C, 53.2; H, 6.47; S, 8.70. The2-chloro-4-isopropylamino-5-methyl-thieno[3,4-d] pyrimidine used as thestarting product is a new compound prepared, with a yield of 80% from2,4-dichloro- S-methyl-thieno[3,4-d]pyrimidine and isopropylamineaccording to the process described in Example 1. M.P. 118- 119 C.(recrystallized from toluene).

Analysis.-Calculated for C H N ClS (M.W. 241.75) (percent): N, 17.36;Cl, 14.66; S, 13.26; C, 49.65; H, 5.00. Found (percent): N, 17.52; Cl,14.85; S, 13.50; C, 49.3; H, 4.79.

The 2,4-dichloro-5-methyl-thieno 3,4-d] pyrimidine used above is also anew compound obtained from2,4-dihydroxy-5-methyl-thieno[3,4-d]pyrimidine and phosphorusoxychloride at reflux temperature in the presence ofN,N-diethyl-aniline. It is easily purified by sublimation. Yield ofsublimed product: more than 83%. M.P. 134- 136 C.

Analysis.Calculated for C7H4C12N2S (M.W. 219.1) (percent): N, 12.80; C,38.35; H, 1.84; S, 14.62; Cl, 32.35. Found (percent): N, 12.30; C,38.70; H, 2.00; S, 14.32; Cl, 32.00.

The 2,4 dihydroxy-S-methyl-thieno[3,4-d]pyrimidine 10 used above is alsoa new compound prepared from 3- carbethoxy-2-methyl-4-ureido-thiopheneby heating under reflux with concentrated hydrochloric acid in absoluteethyl alcohol. Yield reaches 70%. M.P. 300 C.

Analysis.-Calculated for C7H N O S (M.W. 182.2) (percent): N, 15.36; C,46.1; H, 3.32; S, 17.60. Found (percent): N, 15.39; C, 45.9; H, 3.51; S,17.45.

The 3-carbethoxy-2-methyl-4-ureido-thiophene used above is also a newcompound prepared from 4-amin0-3 carbethoxy-2-methy1thiophenehydrochloride and potassium cyanate in an aqueous hydrochloric acidmedium. The reaction takes place at room temperature with a yield of89%. M.P. 186192 C.

Analysis.Calculated for C H N O S (M.W. 228.3) (percent): N, 12.28; S,14.05; C, 47.30; H, 5.30. Found (percent): N, 12.26; S, 14.36; C, 47.7;H, 5.38.

The 4-amino-3-earbethoxy-Z-methyl-thiophene hydrochloride is also a newcompound prepared in ether at room temperature from3-carbethoxy-4-hydroxyimin0-2- methyl-tetrahydrothiophene and a solutionof hydrochloric acid in ethyl alcohol. Yield: 40%. Afterrecrystallization from a mixture of ethanol and ether, M.P. C.(decomposes).

Analysis.-Calculated for C H NO S'HCl (M.W. 221.7) (percent): N, 6.31;S, 14.4; Cl, 16.0; C, 43.3; H, 5.45. Found (percent): N, 6.36; S, 14.2;C1, 16.3; C, 43.2; H, 5.63.

Finally the 3-carbethoxy-4-hydroxyirnino2-methyltetrahydrothiophene isprepared in alcohol under reflux with a yield of 91% from the knowncompound 3-carbethoxy 2 methyl 4 oxo-tetrahydrothiophene (Takaya et al.,Bull. Chem. Soc. Japan, 4], (1968), 2086) and hydroxylaminehydrochloride in the presence of barium carbonate.

The 3-carbethoxy-4-hydroxyimino2-methyl-tetrahydrothiophene is an oilyproduct.

Analysis.-Calculated for C H NO S (M.W. 203.3) (percent): N, 6.88; S,15.8. Found (percent): N, 6.96; S, 15.6.

EXAMPLE 9 Preparation of 4-morpholinoQ-n-propyl-thieno[3,4-d] pyrimidine3 g. (0.014 moles) of 4-cl1loro 2 n-propyl-thieno- [3,4-d1pyrimidine isadded in small portions, with thorough agitation, to 12 ml. ofmorpholine cooled to 0 C. The speed of addition must be regulated insuch a way that the temperature of the reaction mixture does not exceed10 C. When the addition is completed, the mixture is allowed to returnto ordinary temperature and the agitation is continued at thistemperature for one hour. The mixture is allowed to stand for 24 hoursand then is poured with agitation into 500 ml. of cold water. The solidwhich is precipitated is drained off, washed with water and dried. It istaken up in methyl alcohol, the methyl alcohol solution is bleached overactive charcoal and the solvent is driven off in vacuo.

2.5 g. (68% of theory) of4-rnorpholino-Z-n-propylthieno[3,4-d]pyrimidine are obtained. M.P.102105 C.

Analysis.-Calculated for C13H17N3OS (M.W. 263.4) (percent): C, 59.2; H,6.50; N, 15.9; S, 12.17. Found (percent): C, 59.1; H, 6.54; N, 15.9: S,12.14.

The monohydrochloride is prepared by dissolving the base in benzene,adding an anhydrous solution of hydrochloric acid in ethyl alcohol andthen adding ether. M.P. 230 C. (decomposes).

Analysis.-Calculated for C H N OS-1HCl (M.W. 299.8) (perecnt): N, 14.0;S, 10.69; Cl, 11.82. Found (percent): N, 13.9; S, 10.23; Cl, 11.83.

The following compounds were prepared in a similar manner:

2-n-propyl 4 (3 methyl-morpholino)-thieno[3,4-d] pyrimidine; M.P. ofmaleate: 144-146 C. (recrystallized from isopropanol) 11 2-n-propyl 4 (4methyl-piperazino)-thieno[3,4-d] pyrimidine; after recrystallizationfrom ethanol M.P. of dimaleate: 189 C. (decomposes) 2-n-propyl 4isopropylamino-thieno[3,4-d]pyrimidine; M.P. of free base: 137-1395 C.(recrystallized from ethylacetate); M.P. of maleate: 132134 C.(recrystallized from ethyl acetate).

The 4 chloro-2-n-propyl-thieno[3,4-d]pyrimidine used as startingmaterial is a new compound prepared by heating for 2 hours at 60 C.,4-hydroxy-2-n-propyl-thieno [3,4-d]pyrimidine with phosphorusoxychloride in the presence of N,N-diethylaniline. Yield reaches 57%.M.P. 78-80" C. (recrystallized from acetonitrile).

Analysis.-Calculated for C H N CIS (M.W. 212.7) (percent): N, 13.16; S,15.07; Cl, 16.66. Found (percent): N, 13.14; S, 15.03; Cl, 16.30.

The 4-hydroxy-2-n-propyl-thieno [3 ,4-d] pyrimidine used above is also anew product prepared by the action of concentrated ammonia at roomtemperature on 2-n-propyl-4-oxo-4H-thieno[3,4-d]-m-oxazine. The pureproduct is obtained with a yield of 65%. M.P. 212214 C. (recrystallizedfrom ethyl acetate).

Analysis.-Calculated for C H N OS (M.W. 194.3) (percent): C, 55.6; H,5.19; N, 14.41; S, 16.50. Found (percent): C, 55.9; H, 5.20; N, 14.42;S, 16.50.

The 2-n-propyl-4-oxo-4H-thieno[3,4-d]-m-oxazine used above is also a newproduct prepared by the action of acetic anhydride at reflux temperatureon 3 butanoylamino-4-thenoic acid. Yield is 50%. M.P.: 101-l03 C.(recrystallized from acetic anhydride) Analysis-Calculated for C H NO S(M.W. 195.2) (percent): N, 7.17; S, 16.42. Found (percent): N, 7.10; S,16.55.

The 3-butanoylamino-4-thenoic acid used above is also a new productprepared by the selective hydrolysis of 3-butanoylamino-4-carbomethoxy-thiophene in a mixture of sodium hydroxide,water and methyl alcohol at ordinary temperature. Yield: 90%. M.P.135138 C.

Analysis.Calculated for C H NO S (M.W. 213.2) (percent): C, 50.7; H,5.20; N, 6.56; S, 15.03. Found (percent): C, 50.9; H, 5.21; N, 6.63; S,15.11.

The 3-butanoylamino-4-carbomethoxy-thiophene used above is also a newproduct prepared by the action of butyric anhydride on3-amino-4-carbomethoxy-thiophene hydrochloride in the presence ofpyridine at ordinary temperature. Yield: 80%. B.P. 120-124 C./0.1 mm.Hg.

Analysis.-Calculate for CHI-113N038 (M.W. 227.2) (percent): C, 52.8; H,5.76; N, 6.16; S, 14.1. Found (percent): C, 53.1; H, 5.77; N, 6.15; S,14.2.

The 3-amino-4-carbomethoxy-thiophene hydrochloride is known from thearticle by B. R. Baker et a1. cited in Example 1 of the presentinvention.

EXAMPLE 10 Preparation of 2,4-diethoxy-thieno[3,4-d] pyrimidine Asolution of 0.06 mole sodium ethyla'te in ethyl alcohol is addeddropwise while cooling to a suspension of 6.15 g. (0.03 mole) of2,4-dichloro-thieno[3,4-d]pyrimidine in 100 ml. absolute ethyl alcohol.The speed of addition is regulated in such a way that the temperature ofthe reaction medium is maintained at between and C. When addition iscompleted, the solution is left to rise to room temperature and is thenheated under reflux for 4 hours. It is then evaporated to dryness. Theremaining solid is drained, washed with water and left to dry. Afterrecrystallization from a 50/50 mixture of ethyl alcohol and water, 2.8g. (42% of theory) of 2,4-diethoxy-thieno [3,4-d]pyrimidine areobtained. M.P. 8486 C.

Analysis.-Calculated for C H N O S (M.W. 224.3) (percent): C, 53.5; H,5.35; N, 12.5; S, 14.8. Found (percent): C, 53.2; H, 5.44; N, 12.6; S,14.5.

12 2,4-dimethoxy-thieno[BA-d]pyrimidine is prepared in the same way.M.P. 131132 C. (recrystallized from methyl alcohol).

EXAMPLE 11 Preparation of 2-ethoxy-4-n-propylarnino-thieno[3,4-d]pyrimidine A solution of 2.3 g. (0.01 mole) of 2,4-diethoxy-thieno-[3,4-d1pyrimidine and 3.6 g. (0.06 mole) of n-propylamine in 50 ml.absolute ethyl alcohol is heated under reflux for 10 hours. The solutionis then evaporated to dryness. The solid is drained 01f, washed withWater and dried. After recrystallization from toluene, 14 g. (59% oftheory) of 2-ethoxy-4-n-propylamino-thieno[3,4-d] pyrimidine areobtained. M.P. -142 C.

Analysis.Calculated for C H N CS (M.W. 237.3) (percent): N, 17.72; S,13.5. Found (percent): N, 17.46; S, 13.8.

This product is easily converted into the hydrochloride in known manner.M.P. of the hydrochloride: 154 C. (decomposes).

Analysis.-Calculated for C H N OS-HCl (M.W. 273.8) (percent): N, 15.34;S, 12.9. Found (percent): N, 15.32; S, 13.0.

2-ethoxy-4-isopropylamino-thieno[3,4 d]pyrimidine is prepared in thesame way. M.P. of the free base: 154- 156 C.; M.P. of the hydrochloride:166 C. (decomp).

EXAMPLE 12 Preparation of 2-ethoxy-4-isopropylamino-thieno[3,4-d]pyrimidine A solution of 4.5 g. (0.02 mole) of2-chloro-4-isopropylamino-thieno[3,4 d]pyrimidine and 0.02 mole sodiumethylate in 200 ml. absolute ethyl alcohols is heated in an autoclave at120 C. for 6 hours. It is then evaporated to dryness. The residue istaken up in a mixture of ether and Water; the ether phase is washed withwater till neutral pH, dried over Na SO filtered and the solvent isdriven 011' in vacuo. The remaining solid (4.4 g.) is recrystallizedfrom a mixture of ethyl acetate-hexane containing 30% ethyl acetate. 3.2g. (68% of theory) of 2-ethoxy-4-isopropylamino-thieno[3,4 d]pyrimidineare obtained. M.P. -156 C.

Analysis.-Calculated for C H N OS (M.W. 237.3) (percent): N, 17.72; S,13.5. Found (percent): N, 17.44; S, 13.9.

This compound was compared with that prepared in Example 11 and whichmelted at 154l56 C. The identity of both substances was confirmed by thetest of mixture M.P. and by IR spectroscopy.

I claim:

11. A compound selected from the group consisting of those of theformula:

13 14 3. The compound according to claim 1, namely, 2- References Citedchloro 4 (2 methyl morpholino) thieno[3, B. R. Baker, et a1.: ChemicalAbstracts, vol. 48, pp. pyrimidine. 1370-1371 (1954).

The compound according to Claim namely, Robba Max et 211.: ChemicalAbstracts, vol. 69, 27365j chloro 4 (3 methyl morpholino) thieno[3,4 d]5 (1968). pyrimidine. Robba Max et 211.: Chemical Abstracts, Vol. 69',96635j.

5. The compound according to claim 1, namely, 2- n chloro 4 (3methyl-morpholino) 5 methyl-thieno- NICHOLAS RIZZOB Pnmary Exammer[3,4-djpyrimidine. 10 J. TOVAR, Assistant Examiner 6. The compoundaccording to claim 1, namely, 2-npropyl 4 (3 methyl morpholino)thieno[3,4 d] CL pyrimidine. 260-251 R, 256.4 F, 256.5 R; 424-248

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THEFORMULA: